CN110483418A - 3-取代喹唑啉酮-2-甲酰胺衍生物及其制备方法和应用 - Google Patents
3-取代喹唑啉酮-2-甲酰胺衍生物及其制备方法和应用 Download PDFInfo
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- CN110483418A CN110483418A CN201910859465.5A CN201910859465A CN110483418A CN 110483418 A CN110483418 A CN 110483418A CN 201910859465 A CN201910859465 A CN 201910859465A CN 110483418 A CN110483418 A CN 110483418A
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- carboxamides derivatives
- substituted quinazoline
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- -1 3- substituted quinazoline ketone Chemical class 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
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- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 claims abstract 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 6
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
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- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
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- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
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- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/92—Oxygen atoms with hetero atoms directly attached to nitrogen atoms of the hetero ring
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明提供了一种3‑取代喹唑啉酮‑2‑甲酰胺衍生物及其制备方法和应用,通式为
Description
技术领域
本发明涉及有机化学及药物化学技术领域,具体涉及3-取代喹唑啉酮-2-甲酰胺衍生物及其制备方法和应用。
背景技术
炎症是机体受到外界致炎因子刺激时所发生的生理和病理性反应,炎症作为有益的防御反应一般情况下对机体抵抗外界刺激具有重要意义,但是过度和持续的炎症反应则会导致机体组织损伤,甚至会诱发高血压、动脉粥样硬化、癌症及阿尔兹海默症等严重疾病,因此发现具有潜在抗炎新药研发前景的新骨架及新化合物具有重要意义。
目前抗炎类药物分为甾体抗炎药和非甾体类抗炎药两大类,其中非甾体类抗炎药物的研发更是受到广泛关注,喹唑啉酮类化合物是一类重要的杂环化合物,具有广泛生物活性(World Journal of Pharmacy and Pharmaceutical Sciences2018,7(4),628-649.;Fitoterapia,2017,119,136–149),但目前文献报道的具有抗炎活性的喹唑啉类化合物还比较少,主要包含以下喹唑啉酮化合物A-D。
相关的报道文献包括1.Orient.J.Chem.,2017,33(2),707-716;2.ResearchJ.Pharmac.,Biolog.Chem.Sci.2016,7(2),856-860.;3.Med.Chem.Research 2016,25(10),2143-2154.;4.Bioorg.Med.Chem.2016,24,3818–3828;Eur.J.Med.Chem.,2016,121,410-421.;5.PharmaChemica,2016,8(2),210-215.;6.J.Heterocyclic Chem.,2016,53,1371-1377;7.Bioorg.Med.Chem.Lett.2015,25(5),1072-1077.;Bioorg.Med.Chem.2003,11(23),5293–5299。
发明内容
本发明提供了一种3-取代喹唑啉酮-2-甲酰胺衍生物及其制备方法和应用,发现了更多的3-取代喹唑啉酮-2-甲酰胺衍生物,该类衍生物以靛红酸酐、芳基肼或苄胺类化合物、草酸二乙酯及二胺类化合物等为原料来合成,且这类化合物具有良好的潜在抗炎活性。
具有通式(Ⅰ)的3-取代喹唑啉酮-2-甲酰胺衍生物:
其中,R1为氢、卤素、三氟甲基或磺酰胺基,X为NH或CH2,R2为双烷基氨基、氨基、含氮杂环、芳基或烷基,n为1-5中一数字。
优选的,X为CH2时,R1为氯或溴,R2为N(CH3)2、N(C2H5)2、氨基或X为NH时,R1为氢、氯、氟、三氟甲基、甲基或磺酰胺基,R2为N(CH3)2、N(C2H5)2、氨基、对甲基苯基、(C1-C4)-烷基或
具有通式(Ⅰ)的3-取代喹唑啉酮-2-甲酰胺衍生物的制备方法,包括以下步骤:
S1.靛红酸酐与水反应得
S2.与草酸二乙酯反应得
S3.与H2N(CH2)nR2在乙醇的催化作用下,反应得具有通式(Ⅰ)的3-取代喹唑啉酮-2-甲酰胺衍生物。
进一步的,所述步骤S2的反应是在加热回流的条件下进行的。
进一步的,所述步骤S3的反应是在氮气或惰性气体保护、加热回流的条件下进行的。
优选的,所述步骤S1中,反应完成后,抽滤,用水洗涤,收集滤饼,得的粗产品。
优选的,所述步骤S2中,反应完成后,除去溶剂,硅胶柱层析分离,即将提纯。
优选的,所述步骤S3中,反应完成后,除去溶剂,硅胶柱层析分离,即将通式(Ⅰ)的3-取代喹唑啉酮-2-甲酰胺衍生物提纯。
本发明还进一步提供了具有通式(Ⅰ)的3-取代喹唑啉酮-2-甲酰胺衍生物或以上制备所得的具有通式(Ⅰ)的3-取代喹唑啉酮-2-甲酰胺衍生物在制备抗炎类药物中的应用。
优选的,所述抗炎类药物为非甾体抗炎类药物。
本发明提供了更多的3-取代喹唑啉酮-2-甲酰胺衍生物,为3-取代喹唑啉酮-2-甲酰胺衍生物的研发提供了更广阔的的思路。
本发明发展了以靛红酸酐、芳基肼或苄胺类化合物、草酸二乙酯及二胺类化合物等为原料来合成3-取代喹唑啉酮-2-甲酰胺衍生物的路线,提供了一种3-取代喹唑啉酮-2-甲酰胺衍生物制备方法,为3-取代喹唑啉酮-2-甲酰胺衍生物的合成提供了更广阔的思路。
经试验证明,本发明所提供的3-取代喹唑啉酮-2-甲酰胺衍生物,在外显示良好的潜在抗炎活性,为进一步开发出更多新型非甾体抗炎类药物提供了更好的前景,为新型非甾体抗炎药物的研发提供了更多选择。
具体实施方式
以下将结合具体实施例对本发明作进一步说明,但本发明的保护范围不限于以下实施例。
以下实施例的合成路线见Scheme 1:
本实施例涉及的具有通式(Ⅰ)的3-取代喹唑啉酮-2-甲酰胺衍生物具体包括:
下面结合实施例对本发明作进一步说明。需要说明的是,下述实施例仅用于说明,而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1化合物3a的合成
在电磁搅拌下,将靛红酸酐(3.06mmol,500mg)、水(10mL)和对氯苄胺(3.06mmol,434mg)依次加入到50mL圆底烧瓶中,让混合物常温反应12h(TLC监测反应,展开剂:DCM),反应完全,抽滤,用水洗涤(3×5mL),收集滤饼,得到702mg的白色固体化合物3a产率88%。
实施例2化合物3b的合成
用对溴苄胺替换实施例1的对氯苄胺,实验操作与实施例1相同,得化合物3b
实施例3化合物3c的合成
用苯肼替换实施例1的对氯苄胺,实验操作与实施例1相同,得化合物3c
实施例4化合物3d的合成
用对氯苯肼替换实施例1的对氯苄胺,实验操作与实施例1相同,得化合物3d
实施例5化合物3e的合成
用对氟苯肼替换实施例1的对氯苄胺,实验操作与实施例1相同,得化合物3e
实施例6化合物3f的合成
用对三氟甲基苯肼替换实施例1的对氯苄胺,实验操作与实施例1相同,得化合物3f
实施例7化合物3g的合成
用对甲基苯肼替换实施例1的对氯苄胺,实验操作与实施例1相同,得化合物3f
实施例8化合物3h的合成
用对磺酰胺基苯肼替换实施例1的对氯苄胺,实验操作与实施例1相同,得化合物3h
实施例2-8合成化合物3b-3h,产率66-92%。
实施例9化合物4a的合成
在电磁搅拌下,将化合物3a(2.69mmol,700mg)和草酸二乙酯(26.9mmol,4mL)依次加入到50mL圆底烧瓶中,让混合物加热回流反应4h(TLC监测反应,展开剂:V二氯甲烷:V乙酸乙酯=10:1),反应完全,减压除去溶剂,所得粗产物经硅胶柱层析提纯,得到916mg的白色固体化合物4a产率99%。
实施例10化合物4b的合成
用化合物3b替换化合物3a,实验操作与实施例9相同,得化合物4b
实施例11化合物4c的合成
用化合物3c替换化合物3a,实验操作与实施例9相同,得化合物4c
实施例12化合物4d的合成
用化合物3d替换化合物3a,实验操作与实施例9相同,得化合物4d
实施例13化合物4e的合成
用化合物3e替换化合物3a,实验操作与实施例9相同,得化合物4e
实施例14化合物4f的合成
用化合物3f替换化合物3a,实验操作与实施例9相同,得化合物4f
实施例15化合物4g的合成
用化合物3g替换化合物3a,实验操作与实施例9相同,得化合物4g
实施例16化合物4h的合成
用化合物3h替换化合物3a,实验操作与实施例9相同,得化合物4h
实施例10-16合成化合物4b-4h,产率86-98%。
实施例17化合物5a的合成与表征
在电磁搅拌下,将化合物4a(0.31mmol,200mg)、N,N-二甲基乙二胺(1.55mmol,0.2mL)和乙醇(5mL)依次加到50mL圆底烧瓶中,将混合物加热回流反应1h(TLC监测反应,展开剂:V甲醇:V二氯甲烷=1:10),反应完全,减压除去溶剂,所得粗产物经硅胶柱层析提纯,得到88mg的白色固体化合物5a。
3-(4-Chlorobenzyl)-N-(2-(dimethylamino)ethyl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide(5a).白色固体,88mg,74%产率,熔点:174~177℃.1H NMR(400MHz,CDCl3)δ12.64(s,1H),8.59(d,J=8.3Hz,1H),7.88(s,1H),7.54(d,J=7.8Hz,1H),7.50–7.42(m,1H),7.26(s,2H),7.13–7.06(m,1H),6.82(s,1H),4.58(d,J=5.8Hz,2H),3.47–3.39(m,2H),2.50(t,J=6.1Hz,2H),2.27(s,6H).13C NMR(100MHz,CDCl3)δ168.0,159.9,158.3,138.0,136.4,133.4,132.6,129.3,128.8,126.8,123.9,121.4,121.1,57.4,45.1,43.2,37.2.HRMS(ESI)m/z calcd for C20H22N4O2Cl[M+H]+385.1426,found385.1418。
实施例18化合物5b的合成与表征
用N,N-二乙基乙二胺替换实施例17中的N,N-二甲基乙二胺,实验操作与实施例17相同,得化合物5b。
3-(4-Chlorobenzyl)-N-(2-(diethylamino)ethyl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide(5b).白色固体,103.5mg,43%产率,熔点:152~154℃.1H NMR(500MHz,CDCl3)δ12.66(s,1H),8.65–8.61(m,1H),7.95(s,1H),7.56–7.47(m,2H),7.32–7.29(m,2H),7.15–7.10(m,2H),6.64(s,1H),4.61(d,J=5.8Hz,2H),3.41(q,J=6.0Hz,2H),2.63(t,J=6.2Hz,2H),2.57(q,J=7.1Hz,4H),1.04(t,J=7.1Hz,6H).13C NMR(125MHz,CDCl3)δ167.9,159.7,158.4,138.1,136.3,133.5,132.6,129.4,128.9,126.7,123.9,121.4,121.2,51.2,46.9,43.3,37.4,11.8.HRMS(ESI)m/z calcd for C22H25N4O2Cl[M+H]+413.1739,found413.1751。
实施例19化合物5d的合成与表征
用N,N-二甲基-1,3-丙二胺替换实施例17中的N,N-二甲基乙二胺,实验操作与实施例17相同,得化合物5d。
3-(4-Chlorobenzyl)-N-(3-(dimethylamino)propyl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide(5d).白色固体,83.8mg,36%产率,熔点:130~131℃.1H NMR(500MHz,CD3OD)δ8.58(d,J=8.3Hz,1H),7.77–7.71(m,1H),7.55–7.49(m,1H),7.37–7.30(m,4H),7.24–7.18(m,1H),4.55(s,2H),3.36(t,J=6.9Hz,2H),2.55–2.47(m,2H),2.35(s,6H),1.86–1.76(m,2H).13C NMR(125MHz,CD3OD)δ167.3,159.0,156.5,136.0,135.7,131.0,130.3,127.3,126.7,126.1,122.3,120.7,119.0,55.0,42.2,40.7,36.0,24.6.HRMS(ESI)m/z calcd for C21H23N4O2Cl[M+H]+399.1570,found 399.1588。
实施例20化合物5e的合成与表征
用N,N-二乙基-1,3-丙二胺替换实施例17中的N,N-二甲基乙二胺,实验操作与实施例17相同,得化合物5e。
3-(4-Chlorobenzyl)-N-(3-(diethylamino)propyl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide(5e).白色固体,120.2mg,49%产率,熔点:92~94℃.1H NMR(500MHz,CDCl3)δ12.60(s,1H),8.87(s,1H),8.62–8.58(m,1H),7.55–7.51(m,1H),7.50–7.44(m,1H),7.30–7.28(m,2H),7.13–7.07(m,1H),6.81–6.66(m,1H),4.60(d,J=5.8Hz,2H),3.47–3.42(m,2H),2.60–2.54(m,6H),1.78–1.69(m,2H),1.08(t,J=7.1Hz,6H).13C NMR(125MHz,CDCl3)δ167.9,159.8,158.5,138.1,136.4,133.4,132.5,129.4,128.8,126.8,123.8,121.4,121.2,51.9,46.8,43.2,39.8,25.4,11.3.HRMS(ESI)m/zcalcd for C23H27N4O2Cl[M+H]+427.1895,found427.1306。
实施例21化合物5f的合成与表征
用替换实施例17中的N,N-二甲基乙二胺,实验操作与实施例17相同,得化合物5f。
3-(4-Chlorobenzyl)-4-oxo-N-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinazoline-2-carboxamide(5f).白色固体,185mg,75%产率,熔点:115~117℃.1H NMR(500MHz,CD3OD)δ8.60–8.55(m,1H),7.76–7.72(m,1H),7.56–7.50(m,1H),7.39–7.30(m,4H),7.25–7.20(m,1H),4.56(s,2H),3.37(t,J=6.8Hz,2H),2.70–2.57(m,6H),1.90–1.80(m,6H).13C NMR(125MHz,DMSO-d6)δ169.3,160.8,158.5,137.9,137.6,133.0,132.2,129.3,128.6,128.0,124.3,122.7,120.9,54.02,53.98,42.6,38.3,27.9,23.2.HRMS(ESI)m/z calcd for C23H25N42O2Cl[M+H]+425.1739,found425.1725。
实施例22化合物5h的合成与表征
用1,4-丁二胺替换实施例17中的N,N-二甲基乙二胺,实验操作与实施例17相同,得化合物5h。
N-(4-Aminobutyl)-3-(4-chlorobenzyl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide(5h).白色固体,107mg,48%产率,熔点:219~221℃.1H NMR(400MHz,CD3OD)δ8.58(d,J=7.6Hz,1H),7.77–7.71(m,1H),7.56–7.50(m,1H),7.38–7.28(m,4H),7.25–7.18(m,1H)),4.55(s,2H),3.34(t,J=6.6Hz,2H),2.77(t,J=7.1Hz,2H),1.69–1.52(m,4H).13CNMR(125MHz,CD3OD)δ177.2,169.0,167.9,147.7,147.1,141.7,140.9,138.6,137.83,137.77,133.2,130.7,129.6,51.4,49.9,38.5,38.2,35.5.HRMS(ESI)m/z calcd forC20H22N4O2Cl[M+H]+385.1426,found 385.1415。
实施例23化合物6a的合成与表征
用化合物4b替换实施例17中的化合物4a,实验操作与实施例17相同,得化合物6a。
3-(4-Bromobenzyl)-N-(2-(dimethylamino)ethyl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide(6a).白色固体,205mg,92%产率,熔点:184~186℃.1H NMR(500MHz,CD3OD)δ8.58(d,J=8.4Hz,1H),7.78–7.69(m,1H),7.57–7.51(m,1H),7.48(d,J=8.4Hz,2H),7.31(d,J=8.4Hz,2H),7.25–7.19(m,1H),4.54(s,2H),3.47(t,J=6.6Hz,2H),2.57(t,J=6.6Hz,2H),2.32(s,6H).13C NMR(125MHz,CD3OD)δ170.3,161.9,159.4,139.4,138.6,133.2,132.6,130.6,129.0,125.3,123.7,122.0,121.9,58.9,45.4,43.7,38.2.HRMS(ESI)m/z calcd for C20H22N4O2Br[M+H]+429.0921,found429.0927。
实施例24化合物6b的合成与表征
用N,N-二乙基乙二胺替换实施例23中的N,N-二甲基乙二胺,实验操作与实施例23相同,得化合物6b。
3-(4-Bromobenzyl)-N-(2-(diethylamino)ethyl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide(6b).白色固体,212mg,89%产率,熔点:157~159℃.1H NMR(400MHz,CD3OD)δ8.61–8.53(m,1H),7.77–7.71(m,1H),7.57–7.50(m,1H),7.50–7.43(m,2H),7.29(d,J=8.4Hz,2H),7.25–7.17(m,1H),4.53(s,2H),3.43(t,J=7.0Hz,2H),2.74–2.58(m,6H),1.08(t,J=7.2Hz,6H).13C NMR(100MHz,CD3OD)δ170.3,161.8,159.4,139.4,138.7,133.2,132.6,130.6,129.1,125.3,123.7,121.93,121.91,52.2,48.1,43.7,38.0,11.6.HRMS(ESI)m/z calcd for C22H26N4O2Br[M+H]+457.1234,found457.1215。
实施例25化合物6d的合成与表征
用N,N-二甲基-1,3-丙二胺替换实施例23中的N,N-二甲基乙二胺,实验操作与实施例23相同,得化合物6d。
3-(4-Bromobenzyl)-N-(3-(dimethylamino)propyl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide(6d).白色固体,185mg,75%产率,熔点:128~130℃.1H NMR(500MHz,CD3OD)δ8.58(d,J=8.3Hz,1H),7.76–7.70(m,1H),7.55–7.50(m,1H),7.46(d,J=8.4Hz,2H),7.29(d,J=8.4Hz,2H),7.21(t,J=7.6Hz,1H),4.53(s,2H),3.35(t,J=6.9Hz,2H),2.49–2.42(m,2H),2.31(s,6H),1.82–1.75(m,2H).13C NMR(125MHz,CD3OD)δ170.3,161.8,159.5,139.4,138.7,133.2,132.6,130.6,129.0,125.2,123.6,121.91,121.89,58.0,45.2,43.7,39.0,27.6.HRMS(ESI)m/z calcd for C21H24N4O2Br[M+H]+443.1063,found443.1074。
实施例26化合物6e的合成与表征
用N,N-二乙基-1,3-丙二胺替换实施例23中的N,N-二甲基乙二胺,实验操作与实施例23相同,得化合物6e。
3-(4-Bromobenzyl)-N-(3-(diethylamino)propyl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide(6e).白色固体,220mg,90%产率,熔点:99~101℃.1H NMR(400MHz,CD3OD)δ8.60–8.54(m,1H),7.76–7.70(m,1H),7.56–7.50(m,1H),7.49–7.44(m,2H),7.33–7.27(m,2H),7.24–7.18(m,1H),4.53(s,2H),3.35(t,J=6.8Hz,2H),2.65–2.54(m,6H),1.81–1.72(m,2H),1.07(t,J=7.2Hz,6H).13C NMR(100MHz,CD3OD)δ170.3,161.8,159.5,139.4,138.7,133.2,132.6,130.6,129.1,125.3,123.6,121.92,121.90,51.5,47.7,43.7,39.5,26.6,11.2.HRMS(ESI)m/z calcd for C23H28N4O2Br[M+H]+471.1390,found471.1208。
实施例27化合物6f的合成与表征
用替换实施例23中的N,N-二甲基乙二胺,实验操作与实施例23相同,得化合物6f。
3-(4-Bromobenzyl)-4-oxo-N-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinazoline-2-carboxamide(6f).白色固体,229mg,94%产率,熔点:106~108℃.1H NMR(400MHz,CD3OD)δ8.61–8.54(m,1H),7.76–7.72(m,1H),7.56–7.50(m,1H),7.49–7.43(m,2H),7.32–7.26(m,2H),7.24–7.17(m,1H),4.53(s,2H),3.37(t,J=6.8Hz,2H),2.69–2.57(m,6H),1.88–1.77(m,6H).13C NMR(100MHz,CD3OD)δ170.3,161.8,159.5,139.4,138.7,133.2,132.6,130.6,129.1,125.3,123.6,121.9,55.0,54.9,43.7,39.2,28.9,24.2.HRMS(ESI)m/z calcd for C23H26N4O2Br[M+H]+469.1234,found469.1234。
实施例28化合物6g的合成与表征
用1,3-丙二胺替换实施例23中的N,N-二甲基乙二胺,实验操作与实施例23相同,得化合物6g。
N-(3-Aminopropyl)-3-(4-bromobenzyl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide(6g).白色固体,201mg,93%产率,熔点:200~201℃.1H NMR(400MHz,CD3OD)δ8.61–8.53(m,1H),7.77–7.69(m,1H),7.57–7.50(m,1H),7.50–7.42(m,2H),7.34–7.26(m,2H),7.25–7.17(m,1H),4.54(s,2H),3.39(t,J=6.8Hz,2H),2.71(t,J=7.0Hz,2H),1.81–1.69(m,2H).13C NMR(100MHz,CD3OD)δ170.3,162.0,159.4,139.4,138.7,133.3,132.6,130.6,129.1,125.3,123.6,121.9,43.7,39.5,38.0,32.6.HRMS(ESI)m/z calcd forC19H20N4O2Br[M+H]+415.0764,found415.0758。
实施例29化合物6h的合成与表征
用1,4-丁二胺替换实施例17中的N,N-二甲基乙二胺,实验操作与实施例23相同,得化合物6h。
N-(4-Aminobutyl)-3-(4-bromobenzyl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide(6g).白色固体,178mg,80%产率,熔点:180~182℃.1H NMR(500MHz,CD3OD)δ8.60–8.55(m,1H),7.76–7.71(m,1H),7.55–7.50(m,1H),7.49–7.44(m,2H),7.29(d,J=8.5Hz,2H),7.24–7.19(m,1H),4.54(s,2H),3.33(t,J=6.3Hz,2H),2.72–2.66(m,2H),1.66–1.58(m,2H),1.55–1.49(m,2H).13C NMR(125MHz,CD3OD)δ170.3,161.8,159.6,139.4,138.9,133.2,132.6,130.6,129.0,125.3,123.7,121.92,121.90,43.7,41.9,40.5,30.5,27.6.HRMS(ESI)m/z calcd for C20H22N4O2Br[M+H]+429.0921,found429.0916。
实施例30化合物7a的合成与表征
用化合物4c替换实施例17中的化合物4a,实验操作与实施例17相同,得化合物7a。
N-(2-(Dimethylamino)ethyl)-4-oxo-3-(phenylamino)-3,4-dihydroquinazoline-2-carboxamide(7a).白色固体,103mg,45%产率,熔点:120~121℃.1H NMR(400MHz,CD3OD)δ8.25–8.18(m,1H),7.93–7.86(m,1H),7.79(d,J=7.8Hz,1H),7.63–7.57(m,1H),7.24–7.16(m,2H),6.89(t,J=7.4Hz,1H),6.79–6.73(m,2H),3.43(s,2H),2.48–2.39(m,2H),2.24(s,6H).13C NMR(100MHz,CD3OD)δ163.5,162.0,154.2,148.0,136.4,130.1,129.2,128.8,127.8,123.6,122.5,114.9,58.5,45.3,38.0.HRMS(ESI)m/zcalcd for C19H22N5O2[M+H]+352.1768,found 352.1765。
实施例31化合物7b的合成与表征
用N,N-二乙基乙二胺替换实施例30中的N,N-二甲基乙二胺,实验操作与实施例30相同,得化合物7b。
N-(2-(Diethylamino)ethyl)-4-oxo-3-(phenylamino)-3,4-dihydroquinazoline-2-carboxamide(7b).白色固体,193mg,98%产率,熔点:82~84℃.1HNMR(500MHz,CD3OD)δ8.23–8.19(m,1H),7.93–7.87(m,1H),7.79(d,J=8.0Hz,1H),7.64–7.58(m,1H),7.24–7.16(m,1H),6.90(t,J=7.4Hz,1H),6.77(d,J=7.7Hz,2H),3.42(s,2H),2.61–2.52(m,1H),1.02(t,J=7.2Hz,6H).13C NMR(125MHz,CD3OD)δ163.5,162.0,154.2,148.0,147.9,136.4,130.1,129.3,128.8,127.8,123.6,122.5,114.9,52.0,48.1,37.7,11.4.HRMS(ESI)m/z calcd for C21H26N5O2[M+H]+380.2081,found 380.2072。
实施例32化合物7c的合成与表征
用替换实施例30中的N,N-二甲基乙二胺,实验操作与实施例30相同,得化合物7c。
N-(2-(1H-indol-3-yl)ethyl)-4-oxo-3-(phenylamino)-3,4-dihydroquinazoline-2-carboxamide(7c).白色固体,240mg,93%产率,熔点:150~152℃.1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),9.13(s,1H),9.00(t,J=5.7Hz,1H),8.17–8.11(m,1H),7.97–7.89(m,1H),7.82(d,J=7.9Hz,1H),7.65–7.59(m,1H),7.49(d,J=7.8Hz,1H),7.33(d,J=8.0Hz,1H),7.21–7.11(m,3H),7.08–7.02(m,1H),6.97(t,J=7.0Hz,1H),6.84(t,J=7.3Hz,1H),6.79(d,J=7.8Hz,2H),3.51–3.40(m,2H),2.87–2.70(m,2H).13CNMR(100MHz,DMSO-d6)δ161.5,160.1,154.1,147.6,147.0,136.7,135.6,129.1,128.2,128.1,127.5,126.8,123.3,122.5,121.4,120.9,118.7,118.6,114.1,111.9,111.7,25.2.HRMS(ESI)m/z calcd for C25H22N5O2[M+H]+424.1768,found424.1537。
实施例33化合物7d的合成与表征
用N,N-二甲基-1,3-丙二胺替换实施例30中的N,N-二甲基乙二胺,实验操作与实施例30相同,得化合物7d。
N-(3-(Dimethylamino)propyl)-4-oxo-3-(phenylamino)-3,4-dihydroquinazoline-2-carboxamide(7d).白色固体,118mg,66%产率,熔点:126~127℃.1H NMR(500MHz,CD3OD)δ8.24–8.19(m,1H),7.93–7.87(m,1H),7.81–7.77(m,1H),7.63–7.58(m,1H),7.24–7.18(m,2H),6.94–6.87(m,1H),6.82–6.77(m,2H),3.40(s,2H),2.40–2.31(m,2H),2.19(s,6H),1.75–1.64(m,2H).13C NMR(125MHz,CD3OD)δ162.8,160.9,153.4,147.2,147.0,135.4,129.2,128.2,127.8,126.8,122.6,121.6,113.2(s),56.5,44.0,37.3,26.5.HRMS(ESI)m/z calcd for C20H24N5O2[M+H]+366.1925,found 366.1918。
实施例34化合物7e的合成与表征
用N,N-二乙基-1,3-丙二胺替换实施例30中的N,N-二甲基乙二胺,实验操作与实施例30相同,得化合物7e。
N-(3-(Diethylamino)propyl)-4-oxo-3-(phenylamino)-3,4-dihydroquinazoline-2-carboxamide(7e).淡黄色液体,182mg,94%产率.1H NMR(500MHz,CD3OD)δ8.26–8.19(m,1H),7.96–7.89(m,1H),7.83–7.79(m,1H),7.66–7.61(m,1H),7.27–7.19(m,2H),6.93(t,J=7.4Hz,1H),6.86–6.80(m,2H),3.52–3.36(m,2H),2.70–2.58(m,6H),1.80–1.70(m,2H),1.07(t,J=7.2Hz,6H).13C NMR(125MHz,CD3OD)δ162.9,160.9,153.3,147.2,146.9,135.4,129.2,128.2,127.8,126.8,122.6,121.7,114.0,50.2,46.8,37.4,25.4,9.6.HRMS(ESI)m/z calcd for C22H28N5O2[M+H]+394.2235,found 394.2235。
实施例35化合物7f的合成与表征
用替换实施例30中的N,N-二甲基乙二胺,实验操作与实施例30相同,得化合物7f。
4-Oxo-3-(phenylamino)-N-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinazoline-2-carboxamide(7f).白色固体,249mg,98%产率,熔点:109~111℃.1H NMR(500MHz,CD3OD)δ8.23(d,J=7.7Hz,1H),7.91(t,J=7.2Hz,1H),7.81(d,J=8.1Hz,1H),7.62(t,J=7.5Hz,1H),7.23(t,J=7.9Hz,2H),6.92(t,J=7.4Hz,1H),6.81(d,J=7.9Hz,2H),3.54–3.34(m,2H),3.50–3.39(m,6H),1.83–1.71(m,6H).13C NMR(125MHz,CD3OD)δ162.3,160.6,153.1,146.8,146.6,135.0,128.8,127.8,127.4,126.4,122.2,121.2,113.5,53.4,53.3,37.3,27.6,22.7.HRMS(ESI)m/z calcd for C22H26N5O2[M+H]+392.2081,found392.2079。
实施例36化合物7g的合成与表征
用1,3-丙二胺替换实施例30中的N,N-二甲基乙二胺,实验操作与实施例30相同,得化合物7g。
N-(3-Aminopropyl)-4-oxo-3-(phenylamino)-3,4-dihydroquinazoline-2-carboxamide(7g).白色固体,201mg,93%产率,熔点:82~84℃.1H NMR(500MHz,CD3OD)δ8.26–8.16(m,1H),7.94–7.85(m,1H),7.82–7.77(m,1H),7.61(t,J=7.6Hz,1H),7.21(t,J=8.0Hz,2H),6.90(t,J=7.4Hz,1H),6.78(d,J=7.8Hz,2H),3.44–3.33(m,21H),2.59(t,J=7.0Hz,2H),1.71–1.57(m,2H).13C NMR(125MHz,CD3OD)δ160.9,159.0,151.5,145.2,145.0,133.5,127.2,126.3,125.8,124.8,120.7,119.6,111.9,36.4,34.6,29.6.HRMS(ESI)m/z calcd for C18H20N5O2[M+H]+338.1612,found 338.1607。
实施例37化合物7h的合成与表征
用1,4-丁二胺替换实施例30中的N,N-二甲基乙二胺,实验操作与实施例30相同,得化合物7h。
N-(4-Aminobutyl)-4-oxo-3-(phenylamino)-3,4-dihydroquinazoline-2-carboxamide(7h).白色固体,218mg,96%产率,熔点:204~206℃.1H NMR(400MHz,CD3OD)δ8.25–8.15(m,1H),7.94–7.87(m,1H),7.82–7.76(m,1H),7.65–7.57(m,1H),7.26–7.17(m,2H),6.93–6.87(m,1H),6.82–6.75(m,2H),3.42–3.31(m,2H),2.51(t,J=7.1Hz,2H),1.53–1.44(m,2H),1.41–1.32(m,2H).13C NMR(101MHz,CD3OD)δ162.2,160.6,153.2,146.8,146.6,135.0,128.7,127.8,127.4,126.4,122.2,121.1,113.4,40.6,38.6,29.2,26.0.HRMS(ESI)m/z calcd for C19H22N5O2[M+H]+352.1768,found352.1764。
实施例38化合物7i的合成与表征
用替换实施例30中的N,N-二甲基乙二胺,实验操作与实施例30相同,得化合物7i。
N-(4-Methylbenzyl)-4-oxo-3-(phenylamino)-3,4-dihydroquinazoline-2-carboxamide(7i).白色固体,354mg,92%产率,熔点:108~110℃.1H NMR(400MHz,CD3OD)δ9.29(t,J=5.9Hz,1H),9.25(s,1H),8.15(d,J=7.9Hz,1H),7.98–7.88(m,1H),7.81(d,J=8.0Hz,1H),7.62(t,J=7.2Hz,1H),7.24–7.14(m,2H),7.11–6.95(m,4H),6.85(t,J=7.3Hz,1H),6.78(d,J=7.8Hz,2H),4.50–4.22(m,2H),2.25(s,3H).13C NMR(100MHz,CD3OD)δ161.2,159.6,153.6,147.1,146.5,135.8,135.2,129.1,128.7,128.6,127.8,127.6,126.9,126.4,122.0,120.5,113.5,41.6,20.7.HRMS(ESI)m/z calcd for C23H21N4O2[M+H]+385.1659,found 385.1432。
实施例39化合物7j的合成与表征
用正己胺替换实施例30中的N,N-二甲基乙二胺,实验操作与实施例30相同,得化合物7j。
N-Hexyl-4-oxo-3-(phenylamino)-3,4-dihydroquinazoline-2-carboxamide(7j).白色固体,288mg,82%产率,熔点:113~114℃.1H NMR(500MHz,CD3OD)δ8.24–8.18(m,1H),7.92–7.85(m,1H),7.82–7.76(m,1H),7.63–7.56(m,1H),7.22–7.16(m,2H),6.93–6.84(m,1H),6.81–6.75(m,2H),3.31–3.16(m,2H),1.47–1.41(m,2H),1.27–1.16(m,6H),0.86(t,J=7.0Hz,3H).13C NMR(125MHz,CD3OD)δ162.2,160.6,153.2,146.7,146.6,135.0,128.7,127.8,127.4,126.3,122.2,121.1,113.5,39.0,31.3,28.7,26.1,22.2,13.0.HRMS(ESI)m/z calcd for C20H23N4O2[M+H]+351.1816,found 351.1607。
实施例40化合物8a的合成与表征
用化合物4d替换实施例17中的化合物4a,实验操作与实施例17相同,得化合物8a。
3-((4-Chlorophenyl)amino)-N-(2-(dimethylamino)ethyl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide(8a).白色固体,169mg,99%产率,熔点:178~180℃.1H NMR(400MHz,CD3OD)δ8.25–8.19(m,1H),7.94–7.86(m,1H),7.79(d,J=7.7Hz,1H),7.65–7.58(m,1H),7.22–7.16(m,2H),6.80–6.73(m,2H),3.45(s,2H),2.50(t,J=6.7Hz,2H),2.29(s,6H).13C NMR(100MHz,CD3OD)δ163.5,161.8,154.0,147.8,147.0,136.5,129.9,129.3,128.8,127.8,127.2,123.6,116.4,58.5,45.3,37.9。
实施例41化合物8d的合成与表征
用N,N-二甲基-1,3-丙二胺替换实施例40中的N,N-二甲基乙二胺,实验操作与实施例40相同,得化合物8d。
3-((4-Chlorophenyl)amino)-N-(3-(dimethylamino)propyl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide(8d).白色固体,157mg,90%产率,熔点:113~115℃.1H NMR(400MHz,CD3OD)δ8.25–8.19(m,1H),7.94–7.87(m,1H),7.79(d,J=7.7Hz,1H),7.64–7.58(m,1H),7.23–7.16(m,2H),6.81–6.74(m,2H),3.48–3.32(m,1H),2.33–2.25(m,2H),2.18(s,6H),1.73–1.63(m,2H).13C NMR(100MHz,CD3OD)δ163.6,161.8,154.3,147.9,147.1,136.5,130.0,129.3,128.8,127.8,127.3,123.6,116.4,57.7,45.2,38.5,27.7。
实施例42化合物9a的合成与表征
用化合物4e替换实施例17中的化合物4a,实验操作与实施例17相同,得化合物9a。
N-(2-(Dimethylamino)ethyl)-3-((4-fluorophenyl)amino)-4-oxo-3,4-dihydroquinazoline-2-carboxamide(9a).白色固体,160mg,94%产率,熔点:100~102℃.1H NMR(400MHz,CD3OD)δ8.23–7.57(m,1H),7.93–7.87(m,1H),7.78(d,J=7.7Hz,1H),7.64–8.19(m,1H),6.98–6.92(m,2H),6.83–6.77(m,2H),3.47(t,J=6.7Hz,2H),3.33–3.28(m,2H),2.55(t,J=6.8Hz,2H),2.32(s,6H).13C NMR(100MHz,CD3OD)δ163.6,162.0,159.5(d,J=236.5Hz),154.1,147.9144.35(d,J=2.3Hz),136.4,129.0(d,J=50.1Hz),127.8,123.6,116.6(d,J=7.8Hz),116.5,116.3,58.5,45.2,37.8。
实施例43化合物9d的合成与表征
用N,N-二甲基-1,3-丙二胺替换实施例42中的N,N-二甲基乙二胺,实验操作与实施例42相同,得化合物9a。
N-(3-(Dimethylamino)propyl)-3-((4-fluorophenyl)amino)-4-oxo-3,4-dihydroquinazoline-2-carboxamide(9d).淡黄色液体,167mg,95%产率.1H NMR(400MHz,CD3OD)δ8.24–8.18(m,1H),7.93–7.86(m,1H),7.82–7.75(m,1H),7.64–7.57(m,1H),6.99–6.91(m,2H),6.86–6.78(m,2H),3.41–3.32(m,2H),2.31–2.23(m,3H),2.15(s,6H),1.73–1.63(m,2H).13C NMR(100MHz,CD3OD)δ163.7,161.9,159.5(d,J=236.4Hz),154.4,148.0,144.50(d,J=2.3Hz),136.4,129.0(d,J=42.5Hz),127.7,123.6,116.6,116.5(d,J=15.2Hz),57.8,45.3,38.6,27.8。
实施例44化合物10a的合成与表征
用化合物4f替换实施例17中的化合物4a,实验操作与实施例17相同,得化合物10a。
N-(2-(dimethylamino)ethyl)-4-oxo-3-((4-(trifluoromethyl)phenyl)amino)-3,4-dihydroquinazoline-2-carboxamide(10a).White solid 172mg,98%yield.1H NMR(400MHz,CD3OD)δ8.26–8.20(m,1H),7.95–7.87(m,1H),7.81(d,J=7.7Hz,1H),7.66–7.59(m,1H),7.38(t,J=8.0Hz,1H),7.18(d,J=7.7Hz,1H),7.11(s,1H),6.99–6.93(m,1H),3.43(s,2H),2.29–2.26(m,2H),2.21(s,6H).13C NMR(100MHz,CD3OD)δ163.9,163.3,161.8,153.9,148.9,147.9,136.5,131.0,129.2(d,J=45.2Hz),127.9,123.5,118.7(d,J=3.9Hz),118.0,111.7(d,J=3.9Hz),58.6,45.4,38.2。
实施例45化合物10d的合成与表征
用N,N-二甲基-1,3-丙二胺替换实施例44中的N,N-二甲基乙二胺,实验操作与实施例44相同,得化合物10d。
N-(3-(Dimethylamino)propyl)-4-oxo-3-((4-(trifluoromethyl)phenyl)amino)-3,4-dihydroquinazoline-2-carboxamide(10d).白色固体,177mg,99%产率,熔点:125~127℃.1H NMR(400MHz,CD3OD)δ1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.92(t,J=5.7Hz,1H),8.19–8.11(m,1H),7.99–7.90(m,1H),7.82(d,J=7.9Hz,1H),7.68–7.60(m,1H),7.39(t,J=7.9Hz,1H),7.22–7.11(m,2H),7.02(d,J=8.2Hz,1H),3.29–3.13(m,2H),2.29(t,J=7.1Hz,2H),2.15(s,6H),1.61–1.50(m,2H).13C NMR(100MHz,CD3OD)δ162.1,160.3,152.8,147.7,146.5,135.2,129.7,127.7(d,J=44.6Hz),126.4,122.1,117.5(d,J=3.9Hz),116.6,110.4(d,J=4.0Hz),56.4,43.9,37.2,26.5。
实施例46化合物11a的合成与表征
用化合物4g替换实施例17中的化合物4a,实验操作与实施例17相同,得化合物11a。
N-(2-(Dimethylamino)ethyl)-4-oxo-3-(p-tolylamino)-3,4-dihydroquinazoline-2-carboxamide(11a).白色固体,172mg,98%产率,熔点:108~110℃.1H NMR(400MHz,CD3OD)δ8.25–8.17(m,1H),7.92–7.86(m,1H),7.78(d,J=7.7Hz,1H),7.63–7.56(m,1H),7.01(d,J=8.1Hz,2H),6.70–6.63(m,2H),3.46–3.39(m,2H),2.40(t,J=6.8Hz,2H),2.23(s,3H),2.21(s,6H).13C NMR(100MHz,CD3OD)δ163.6,162.1154.2,147.9,145.6,136.4,132.0,130.5,129.2,128.8,127.8123.6,115.1,58.5,45.4,38.1,20.6。
实施例47化合物11d的合成与表征
用N,N-二甲基-1,3-丙二胺替换实施例46中的N,N-二甲基乙二胺,实验操作与实施例46相同,得化合物11d。
N-(3-(Dimethylamino)propyl)-4-oxo-3-(p-tolylamino)-3,4-dihydroquinazoline-2-carboxamide(11d).白色固体,122mg,70%产率,熔点:111~113℃.1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.83(t,J=5.7Hz,1H),8.16–8.08(m,1H),7.96–7.88(m,1H),7.79(d,J=7.9Hz,1H),7.64–7.56(m,1H),6.96(d,J=8.3Hz,2H),6.68(d,J=8.4Hz,2H),3.30–3.10(m,2H),2.30(t,J=7.2Hz,2H),2.18(s,3H),2.16(s,6H),1.62–1.49(m,2H).13C NMR(100MHz,DMSO-d6)δ161.1,159.6,153.7,146.5,144.8,135.1,129.2,129.1,127.7,127.6,126.3,122.0,113.7,55.644.2,36.4,25.9,20.1。
实施例48化合物12a的合成与表征
用化合物4h替换实施例17中的化合物4a,实验操作与实施例17相同,得化合物12a。
N-(2-(Dimethylamino)ethyl)-4-oxo-3-((4-sulfamoylphenyl)amino)-3,4-dihydroquinazoline-2-carboxamide(12a).白色固体,122mg,73%产率,熔点:229~231℃.1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),8.78(t,J=5.6Hz,1H),8.18–8.12(m,1H),7.99–7.90(m,1H),7.82(d,J=7.9Hz,1H),7.67–7.58(m,3H),7.12(s,2H),6.87(d,J=8.8Hz,2H),3.30–3.15(m,2H),2.33–2.21(m,2H),2.10(s,6H).13C NMR(100MHz,DMSO-d6)δ160.8,159.4,153.1,150.0,146.4,135.6,135.3,127.9),127.7,126.9,126.5,121.9,112.9,57.5,45.0,36.8。
实施例49效果验证实施例
一、MTT法测试部分化合物对RAW264.7细胞活力的影响实验方法及结果。
本实施例中化合物浓度为100μM。
1.受试细胞的消化及接种
培养受试细胞RAW 264.7(小鼠单核巨噬细胞白血病细胞)至对数期,用0.25%胰蛋白酶进行消化,加入含10%胎牛血清的培养基,无菌塑料吸管吹匀成单细胞悬液,接种到96孔板,每孔加180μL.96孔板四周加200μL PBS缓冲基以减少培养基蒸发。
2.对细胞株加药
本次所有药物包括合成的31个化合物,加上对照药吲哚美辛一共32个药物。
待孔内细胞生长到占整个孔面积约70%时,每孔加药20μL,则药物稀释浓度至100μM,用手轻拍,设5个复孔(平行实验),每块96孔板设置空白孔(不加入药物)和调零孔(含10%胎牛血清的培养基),继续放入培养箱,显微镜下观察细胞的生存情况。
3.测板
加药继续培养48h后,每孔加入10μL的MTT进行染色,用手轻拍,继续培养4~6h,然后弃去孔内的培养基,每孔加入100μL的DMSO,置微型震荡器上震荡10min,使生成的甲臜充分溶解,移至酶联免疫检测仪中检测各孔的吸光值,再用PASW软件处理数据。实验结果见表1.
表1 MTT法检测化合物对RAW264.7细胞活力的影响
化合物 | 存活率(%) | 化合物(%) | 存活率(%) |
5a | 8±0.01 | 7d | 90±0.33 |
5b | 9±0.01 | 7e | 70±0.06 |
5d | 10±0.01 | 7f | 80±0.09 |
5e | 7±0.01 | 7g | 90±0.09 |
5f | 10±0.02 | 7h | 61±0.07 |
5h | 100±0.07 | 7i | 88±0.05 |
6a | 9±0.01 | 7j | 27±0.03 |
6b | 8±0.01 | 8a | 23±0.02 |
6d | 10±0.01 | 8d | 26±0.08 |
6e | 7±0.01 | 9a | 10±0.06 |
6f | 9±0.01 | 9d | 100±0.08 |
6g | 8±0.01 | 10d | 42±0.10 |
6h | 60±0.03 | 11a | 29±0.01 |
7a | 60±0.1 | 11d | 57±0.06 |
7b | 60±0.07 | 12a | 64±0.2 |
7c | 76±0.04 | 吲哚美辛 | 70±0.07 |
在化合物浓度为100μM时,化合物5h、6h、7a、7b、7c、7d、7e、7f、7g、7h、7i、9d、12a的相对存活率较高,因此对这些化合物进行了NO的测试。
二、Griess法测定部分低毒性化合物抑制脂多糖(lipopolysaccharides)LPS)诱导的小鼠巨噬细胞RAW264.7释放NO的抑制作用。
化合物5h、6h、7a、7b、7c、7d、7e、7f、7g、7h、7i、9d、12a对小鼠巨噬细胞RAW 264.7显示了很低的毒性,因此我们进一步测试了这些化合物抑制脂多糖(lipopolysaccharides)LPS)诱导的小鼠巨噬细胞RAW264.7释放NO的作用的实验方法及实验结果:
1.细胞的接种及预处理
将长至对数生长期的RAW 264.7细胞(小鼠单核巨噬细胞白血病细胞)接种于24孔培养板中,每孔400μL,设对照组、LPS应激模型组(1μg/mL LPS)、不同浓度药物实验组(6.25、12.5、25、50μg/m L),对照组和LPS应激模型组模型组添加终浓度为0.1%DMSO的培养基,实验组先用不同浓度药物溶液预处理1h后再添加1μg/mL的LPS共同处理24h,收集细胞上清液。
2.Griess法测定NO释放量
取稀释的系列浓度梯度标准试剂和待测细胞培养上清液至96孔板中,每孔0.05mL,遵照试剂盒说明书进行操作,具体步骤如下:
(1)加入室温状态下的Griess Regent 1试剂,每孔0.05mL,静置10min。
(2)加入室温状态下的Griess Regent 2试剂,每孔0.05mL,静置10min。
(3)于540nm处测定吸光值,得出标准曲线,确定待测样品中NO浓度。
测试结果见表2:
表2部分化合物抑制LPS诱导的小鼠巨噬细胞释放NO作用实验结果
化合物 | NO浓度(μM) | 化合物 | NO浓度(μM) |
5h | 5.83±0.63 | 7f | 6.55±0.49 |
6h | 5.20±0.52 | 7g | 5.27±0.48 |
7a | 4.06±0.62 | 7h | 4.89±0.35 |
7b | 4.67±0.86 | 7i | 3.36±0.83 |
7c | 3.22±0.29 | 9d | 4.61±0.90 |
7d | 3.84±0.90 | 12a | 6.67±0.11 |
7e | 5.64±0.85 | 吲哚美辛 | 3.43±0.91 |
当化合物浓度50mΜ,LPS浓度1μg/mL时,发现化合物7c、7i与对照的抗炎药物吲哚美辛相比较好。因此对这两化合物进行不同浓度梯度的测定。
代表化合物7c和7i在不同浓度下抑制脂多糖(lipopolysaccharides)LPS)诱导的小鼠巨噬细胞NO释放的能力的实验结果如表3、表4:
表3化合物7c对RAW264.7细胞NO释放的影响
表4化合物7i对RAW264.7细胞NO释放的影响
化合物7i的浓度(μmol/L) | NO的浓度(μmol/L) |
0 | 6.35±0.18 |
6.25 | 6.35±0.02 |
12.5 | 3.84±0.26 |
25 | 2.64±0.36 |
50 | 2.26±0.31 |
Claims (10)
1.具有通式(Ⅰ)的3-取代喹唑啉酮-2-甲酰胺衍生物:
其中,R1为氢、卤素、三氟甲基或磺酰胺基,X为NH或CH2,R2为双烷基氨基、氨基、含氮杂环、芳基或烷基,n为1-5中一数字。
2.根据权利要求1所述的具有通式(Ⅰ)的3-取代喹唑啉酮-2-甲酰胺衍生物,其特征在于:
X为CH2时,R1为氯或溴,R2为N(CH3)2、N(C2H5)2、氨基或;X为NH时,R1为氢、氯、氟、三氟甲基、甲基或磺酰胺基,R2为N(CH3)2、N(C2H5)2、氨基、对甲基苯基、、(C1-C4)-烷基或。
3.具有通式(Ⅰ)的3-取代喹唑啉酮-2-甲酰胺衍生物的制备方法,其特征在于包括以下步骤:
S1. 靛红酸酐与、水反应得;
S2. 与草酸二乙酯反应得;
S3. 与H2N(CH2)nR2在乙醇的催化作用下,反应得具有通式(Ⅰ)的3-取代喹唑啉酮-2-甲酰胺衍生物。
4.根据权利要求3所述的制备方法,其特征在于:
所述步骤S2的反应是在加热回流的条件下进行的。
5.根据权利要求3所述的制备方法,其特征在于:
所述步骤S3的反应是在氮气或惰性气体保护、加热回流的条件下进行的。
6.根据权利要求3所述的制备方法,其特征在于:
所述步骤S1中,反应完成后,抽滤,用水洗涤,收集滤饼,得的粗产品。
7.根据权利要求4所述的制备方法,其特征在于:
所述步骤S2中,反应完成后,除去溶剂,硅胶柱层析分离,即将提纯。
8.根据权利要求5所述的制备方法,其特征在于:
所述步骤S3中,反应完成后,除去溶剂,硅胶柱层析分离,即将通式(Ⅰ)的3-取代喹唑啉酮-2-甲酰胺衍生物提纯。
9.权利要求1或2所述的具有通式(Ⅰ)的3-取代喹唑啉酮-2-甲酰胺衍生物或权利要求2~8任一制备所得的具有通式(Ⅰ)的3-取代喹唑啉酮-2-甲酰胺衍生物在制备抗炎类药物中的应用。
10.根据权利要求9所述的应用,其特征在于:所述抗炎类药物为非甾体抗炎类药物。
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